Buccal, polar and non-polar spray or capsule

ABSTRACT

Buccal aerosol sprays or capsule using polar and non-polar solvent have now been developed which provide biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprises formulation I: polar solvent 37-98.58%, active compound 0.005-55%, optionally containing flavoring agent 0.1-10%.

RELATED APPLICATIONS

[0001] This application is a continuation in part of applicant PCTapplication PCT/US97/17899 filed Oct. 1, 1997.

BACKGROUND OF THE INVENTION

[0002] It is known that certain biologically active compounds are betterabsorbed through the oral mucosa than through other routes ofadministration, such as through the stomach or intestine. However,formulations suitable for such administration by these latter routespresent their own problems. For example, the biologically activecompound must be compatible with the other components of the compositionsuch as propellants, solvents, etc. Many such formulations have beenproposed. For example, U.S. Pat. No. 4,689,233, Dvorsky et al.,describes a soft gelatin capsule for the administration of theanti-coronary drug nifedipine dissolved in a mixture of polyetheralcohols. U.S. Pat. No. 4,755,389, Jones et al., describes a hardgelatin chewable capsule containing nifedipine. A chewable gelatincapsule containing a solution or dispersion of a drug is described inU.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda etal, and U.S. Pat. No. 5,370,862, Klokkers-Bethke, describe anitroglycerin spray for administration to the oral mucosa comprisingnitroglycerin, ethanol, and other components. An orally administeredpump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosolcompositions containing a hydrocarbon propellant and a drug foradministration to a mucosal surface are described in U.K. 2,082,457, Su,U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang etal., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted thatthese references discuss bioavailability of solutions by inhalationrather than through the membranes to which they are administered.

SUMMARY OF THE INVENTION

[0003] A buccal aerosol spray or soft bite gelatin capsule using a polaror non-polar solvent has now been developed which provides biologicallyactive compounds for rapid absorption through the oral mucosa, resultingin fast onset of effect.

[0004] The buccal aerosol spray compositions of the present invention,for transmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable non-polar solvent comprise inweight % of total composition: pharmaceutically acceptable propellant5-80%, non-polar solvent 20-85%, active compound 0.05-50%, suitablyadditionally comprising, by weight of total composition a flavoringagent 0.01-10%. Preferably the composition comprises: propellant 10-85%,non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent1-8%; most suitably propellant 20-70%, non-polar solvent 30-74.75%,active compound 0.25-35%, flavoring agent 2-7.5%.

[0005] The buccal polar aerosol spray compositions of the presentinvention, for transmucosal administration of a pharmacologically activecompound soluble in a pharmacologically acceptable polar solvent arealso administrable in aerosol form driven by a propellant. In this casethe composition comprise in weight% of total composition: aqueous polarsolvent 10-99%, active compound 0.1-25%, suitably additionallycomprising, by weight of total composition a flavoring agent 0.05-10%and propellant: 2-10%. Preferably the composition comprises: polarsolvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% andpropellant: 3-5%; most suitably polar solvent 25-97%, active compound0.2-25%, flavoring agent 0.1-2.5% and propellant: 3-4%.

[0006] The buccal pump spray composition of the present invention fortransmucosal administration of a pharmacologically active compound wheresaid active compound is soluble in a pharmacologically acceptablenon-polar solvent said composition comprise in weight % of totalcomposition: non-polar solvent 30-99.69%, active compound 0.005-55%, andsuitably additionally, flavoring agent 0.1-10%.

[0007] The buccal polar pump spray compositions of the presentinvention, for transmucosal administration of a pharmacologically activecompound soluble in a pharmacologically acceptable polar solventcomprising in weight % of total composition: aqueous polar solvent30-99.69%, active compound 0.001-60%, suitably additionally comprising,by weight of total composition a flavoring agent 0.1-10%. Preferably thecomposition comprises: polar solvent 37-98.58%, active compound0.005-55%, flavoring agent 0.5-8%; most suitably polar solvent60.9-97.06%, active compound 0.01-40%, flavoring agent 0.75-7.5%.

[0008] The soft bite gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable non-polarsolvent, having charged thereto a fill composition comprise in weight %of total composition: non-polar solvent 4-99.99%, emulsifier 0-20%,active compound 0.01-80%, provided that said fill composition containsless than 10% of water, suitably additionally comprising, by weight ofthe composition: flavoring agent 0.01-10%. Preferably, the soft bitegelatin capsule comprises: non-polar solvent 21.5-99.975%, emulsifier0-15%, active compound 0.025-70%, flavoring agent 1-8%; most suitably:non-polar solvent 28.5-97.9%, emulsifier 0-10%, active compound0.1-65.0%, flavoring agent 2-6%.

[0009] The soft bite polar gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable polar solvent,having charged thereto a composition comprising in weight % of totalcomposition: polar solvent 25-99.89%, emulsifier 0-20%, active compound0.01-65%, provided that said composition contains less than 10% ofwater, suitably additionally comprising, by weight of the composition:flavoring agent 01-10%. Preferably, the soft bite gelatin capsulecomprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound0.025-55%, flavoring agent 1-8%; most suitably: polar solvent44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent2-6%.

[0010] It is an object of the invention to coat the mucosal membraneseither with extremely fine droplets of spray containing the activecompounds or a solution or paste thereof from bite capsules.

[0011] It is also an object of the invention to administer to the oralmucosa of a mammalian in need of same, preferably man, by spray or bitecapsule. a predetermined amount of a biologically active compound bythis method or from a soft gelatin bite capsule.

[0012] A further object is a sealed aerosol spray container containing acomposition of the non polar or polar aerosol spray formulation, and ametered valve suitable for releasing from said container a predeterminedamount of said composition.

[0013] As the propellant evaporates after activation of the aerosolvalve, a mist of fine droplets is formed which contains solvent andactive compound.

[0014] The propellant is a non-Freon material, preferably a C₃₋₈hydrocarbon of a linear or branched configuration. The propellant shouldbe substantially non-aqueous. The propellant produces a pressure in theaerosol container such that under expected normal usage it will producesufficient pressure to expel the solvent from the container when thevalve is activated but not excessive pressure such as to damage thecontainer or valve seals.

[0015] The non-polar solvent is a non-polar hydrocarbon, preferably aC₇₋₁₈ hydrocarbon of a linear or branched configuration, fatty acidesters, and triglycerides, such as miglyol. The solvent must dissolvethe active compound and be miscible with the propellant, i.e., solventand propellant must form a single phase at 0-4° C. at a pressure rangeof 1-3 atm.

[0016] The polar and non-polar aerosol spray compositions of theinvention are intended to be administered from a sealed, pressurizedcontainer. Unlike a pump spray, which allows the entry of air into thecontainer after every activation, the aerosol container of the inventionis sealed at the time of manufacture. The contents of the container arereleased by activation of a metered valve, will does not allow entry ofatmospheric gasses with each activation. Such containers arecommercially available.

[0017] A further object is a pump spray container containing acomposition of the pump spray formulation, and a metered valve suitablefor releasing from said container a predetermined amount of saidcomposition.

[0018] A further object is a soft gelatin bite capsule containing acomposition of as set forth above. The formulation may be in the form ofa viscous solution or paste containing the active compounds. Althoughsolutions are preferred, paste fills may also be used where the activecompound is not soluble or only partially soluble in the solvent ofchoice. Where water is used to form part of the paste composition, itshould not exceed 10% thereof. (All percentages herein are by weightunless otherwise indicated.)

[0019] The polar or non-polar solvent is-chosen such that it iscompatible with the gelatin shell and the active compound. The solventpreferably dissolves the active compound. However, other componentswherein the active compound is not soluble or only slightly soluble maybe used and will form a paste fill.

[0020] Soft gelatin capsules are well known in the art. See, forexample, U.S. Pat. No. 4,935,243, Borkan et al., for its teaching ofsuch capsules. The capsules of the present invention are intended to bebitten into to release the low viscosity solution or paste therein,which will then coat the buccal mucosa with the active compounds.Typical capsules, which are swallowed whole or bitten and thenswallowed, deliver the active compounds the stomach, which results insignificant lag time before maximum blood levels can be achieved orsubject the compound to a large first pass effect. Because of theenhanced absorption of the compounds through the oral mucosa and nochance of a first pass effect, use of the bite capsules of the inventionwill eliminate much of the lag time, resulting in hastened onset ofbiological effect. The shell of a soft gelatin capsule of the inventionmay comprise, for example:

[0021] Gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%, water5-10%, and sorbitol 2-10%.

[0022] The active compound may include biologically active peptides,central nervous system active amines, sulfonyl ureas, antibiotics,antifungals, antivirals, sleep inducers, antiasthmatics, bronchialdilators, antiemetics, histamine H-2 receptor antagonists, barbiturates,prostaglandins and neutraceuticals.

[0023] The active compounds may also include antihistamines, alkaloids,hormones, benzodiazepines and narcotic analgesics. While not limitedthereto, these active compounds are particularly suitable for non-polarpump spray formulation and application.

BRIEF DESCRIPTION OF THE DRAWING

[0024] The FIGURE is a schematic diagram showing routes of absorptionand processing of pharmacologically active substances in a mammaliansystem.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The preferred active compounds of the present invention are in anionized, salt form or as the free base of the pharmaceuticallyacceptable salts thereof (provided, for the aerosol or spraycompositions, they are soluble in the spray solvent). These compoundsare soluble in the non-polar solvents of the invention at usefulconcentrations or can be prepared as pastes at useful concentrations.These concentrations may be less than the standard accepted dose forthese compounds since there is enhanced absorption of the compoundsthrough the oral mucosa. This aspect of the invention is especiallyimportant when there is a large (40-99.99%) First pass effect.

[0026] As propellants for the non polar sprays, propane, N-butane,iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixturesthereof may be used. N-butane and iso-butane, as single gases, are thepreferred propellants. It is permissible for the propellant to have awater content of no more than 0.2%, typically 0.1-0.2%. (All percentagesherein are by weight unless otherwise indicated.) It is also preferablethat the propellant be synthetically produced to minimize the presenceof contaminants which are harmful to the active compounds. Thesecontaminants include oxidizing agents, reducing agents, Lewis acids orbases, and water. The concentration of each of these should be less than0.1%, except that water may be as high as 0.2%.

[0027] Suitable non-polar solvents for the capsules and the non-polarsprays include (C₂-C₂₄) fatty acid C₂-C₆ esters, C₇-C₁₈ hydrocarbon,C₂-C₆ alkanoyl esters, and the triglycerides of the corresponding acids.When the capsule fill is a paste, other liquid components may be usedinstead of the above low molecular weight solvents. These include soyaoil, corn oil, other vegetable oils.

[0028] As solvents for the polar capsules or sprays there may be usedlow molecular weight polyethyleneglycols (PEG) of 400-1000 Mw(preferably 400-600), low molecular weight (C₂-C₈) mono and polyols andalcohols of C₇-C₁₈ linear or branch chain hydrocarbons, glycerin mayalso be present and water may also be used in the sprays, but only inlimited amount in the capsules.

[0029] It is expected that some glycerin and water used to make thegelatin shell will migrate from the shell to the fill during the curingof the shell. Likewise, there may be some migration of components fromthe fill to the shell during curing and even throughout the shelf-lifeof the capsule. Therefore, the values given herein are for thecompositions as prepared, it being within the scope of the inventionthat minor variations will occur.

[0030] The preferred flavoring agents are synthetic or natural oil ofpepper-mint, oil of spearmint, citrus oil, fruit flavors, sweeteners(sugars, aspartame, saccharin, etc.), and combinations thereof.

[0031] The active substances include the active compounds selected fromthe group consisting of cyclosporine, sermorelin, Octreotide acetate,calcitonin-salmon, insulin lispro, sumatriptan succinate, clozepine,cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine,erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate,cimetidine hydrochloride, famotidine, phenytoin sodium, phenytoin,carboprost thromethamine, carboprost, diphenhydramine hydrochloride,isoproterenol hydrochloride, terbutaline sulfate, terbutaline,theophylline, albuterol sulfate and neutraceuticals, that is to saynutrients with pharmacological action such as but not limited tocarnitine, valerian, echinacea, and the like.

[0032] The formulations of the present invention comprise an activecompound or a pharmaceutically acceptable salt thereof. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids or bases including organicand inorganic acids or bases.

[0033] When an active compound of the present invention is acidic, saltsmay be prepared from pharmaceutically acceptable non-toxic bases. Saltsderived from all stable forms of inorganic bases include aluminum,ammonium, calcium, copper, iron, lithium, magnesium, manganese,potassium, sodium, zinc, etc. Particularly preferred are the ammonium,calcium, magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basicion-exchange resins such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethyl-aminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethyl-piperidine, glucamine, glucosamine,histidine, isopropylamine, lysine, methyl-glucosamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purine, theobromine,triethylamine, trimethylamine, tripropylamine, etc.

[0034] When an active compound of the present invention is basic, saltsmay be prepared from pharmaceutically acceptable non-toxic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric,pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic,maleic, phosphoric, sulfuric, and tartaric acids.

[0035] In the discussion of methods of treatment herein, reference tothe active compounds is meant to also include the pharmaceuticallyacceptable salts thereof. While certain formulations are set forthherein, the actual amounts to be administered to the mammal or man inneed of same are to be determined by the treating physician.

[0036] The invention is further defined by reference to the followingexamples, which are intended to be illustrative and not limiting.

[0037] The following are examples of each class (all values unlessotherwise specified are in weight percent): EXAMPLE 1 Biologicallyactive peptides including peptide hormones most preferred preferredAmounts amount amount A. Cyclosporine lingual spray Cyclosporine  5-5010-35 15-25 water  5-20 7.5-50  9.5-12  ethanol  5-60 7.5-50  10-20polyethylene glycol 20-60 30-45 35-40 flavors 0.1-5   1-4 2-3 B.Cyclosporine Non-Polar lingual spray Cyclosporine  1-50  3-40  5-30Migylol 20 25 30-40 Polyoxyethyl- 20 25 30-40 ated castor oil Butane25-80 30-70 33-50 flavors 0.1-5   1-4 2-3 C. Cyclosporine non-polar bitecapsule Cyclosporine  1-35  5-25 10-20 olive oil 25-60 35-55 30-45polyoxyethyl- 25-60 35-55 30-45 ated oleic glycerides flavors 0.1-5  1-4 2-3 D. Cyclosporine bite capsule Cyclosporine  5-50 10-35 15-25polyethylene glycol 20-60 30-45 35-40 glycerin  5-30 7.5-25  10-20propylene glycol  5-30 7.5-25  10-20 flavors 0.1-10  1-8 3-6 E.Sermorelin (as the acetate) lingual spray sermorelin (as the .01-5  .1-3   .2-1.0 acetate) mannitol,  1-25  5-20 10-15 monobasic sodium0.1-5   1-3 1.5-2.5 phosphate, dibasic sodium 0.01-5   .05-3  0.1-0.5phosphate water ethanol  5-30 7.5-25  9.5-15  polyethylene glycol 20-6030-45 35-40 propylene glycol  5-25 10-20 12-17 flavors 0.1-5   1-4 2-3F. Octreotide acetate (Sandostatin*) lingual spray octreotide acetate0.001-0.5  0.005-0.250 0.01-0.10 acetic acid  1-10 2-8 4-6 sodiumacetate  1-10 2-8 4-6 sodium chloride  3-30  5-25 15-20 flavors 0.1-5  0.5-.4  2-3 ethanol  5-30 7.5-20  9.5-15  water 15-95 35-90 65-85flavors 0.1-5   1-4 2-3 G. Calcitonin-salmon lingual sprayCalcitonin-salmon 0.001-5    0.005-2     01-1.5 ethanol  2-15  3-10  7-9.5 water 30-95 50-90 60-80 polyethylene glycol  2-15  3-10   7-9.5sodium chloride 2.5-20   5-15   10-12.5 flavors 0.1-5   1-4 2-3 H.insulin lispro, lingual spray insulin, 20-60  4-55  5-50 glycerin,0.1-10  0.25-5   0.1-1.5 dibasic sodium  1-15 2.5-10  4-8 phosphate,m-cresol,  1-25  5-25  7.5-12.5 zinc oxide 0.01-0.25  .05-0.150.075-0.10  m-cresol, 0.1-1   0.2-0.8 0.4-0.6 phenol trace amounts traceamounts trace amounts ethanol  5-20 7.5-15   9-12 water 30-90 40-8050-75 propylene glycol  5-20 7.5-15   9-12 flavors 0.1-5   0.5-3  0.75-2   adjust pH to 7.0-7.8 with HCl or NaOH

[0038] EXAMPLE 2 CNS active amines and their salts: including but notlimited to tricyclic amines, GABA analogues, thiazides, phenothiazinederivatives, Serotonin antagonists and serotonin reuptake inhibitorsmost preferred preferred Amounts amount amount A. Sumatriptan succinatelingual spray sumatriptan succinate 0.5-30   1-20 10-15 ethanol  5-607.5-50  10-20 propylene glycol  5-30 7.5-20  10-15 polyethylene glycol 0-60 30-45 35-40 water  5-30 7.5-20  10-15 flavors 0.1-5   1-4 2-3 B.Sumatriptan succinate bite capsule sumatriptan succinate 0.01-5  0.05-3.5  0.075-1.75  polyethylene glycol 25-70 30-60 35-50 glycerin25-70 30-60 35-50 flavors 0.1-10  1-8 3-6 C. Clozepine lingual sprayClozepine 0.5-30   1-20 10-15 ethanol  5-60 7.5-50  10-20 propyleneglycol  5-30 7.5-20  10-15 polyethylene glycol  0-60 30-45 35-40 water 5-30 7.5-20  10-15 flavors 0.1-5   1-4 2-3 D. Clozepine Non-Polarlingual spray with propellant Clozepine 0.5-30   1-20 10-15 Migylol20-85 25-70 30-40 Butane 15-80 30-75 60-70 flavors 0.1-5   1-4 2-3 E.Clozepine Non-Polar lingual spray without propellant Clozepine 0.5-30  1-20 10-15 Migylol   70-99.5 80-99 85-90 flavors 0.1-5   1-4 2-3 F.Cyclobenzaprine Non polar lingual spray Cyclobenzaprine 0.5-30   1-2010-15 (base) Migylol 20-85 25-70 30-40 Iso-butane 15-80 30-75 60-70flavors 0.1-5   1-4 2-3 G. dexfenfluramine hydrochloride lingual spraydexfenfluramine Hcl  5-30 7.5-20  10-15 ethanol  5-60 7.5-50  10-20propylene glycol  5-30 7.5-20  10-15 polyethylene glycol  0-60 30-4535-40 water  5-30 7.5-20  10-15 flavors 0.1-5   1-4 2-3

[0039] EXAMPLE 4 Antibiotics anti-fungals and anti-virals most preferredpreferred Amounts amount amount A. zidovudine [formerly calledazidothymidine (AZT) (Retrovir) non-polar lingual spray zidovudine 10-5015-40 25-35 Soya oil 20-85 25-70 30-40 Butane 15-80 30-75 60-70 flavors0.1-5   1-4 2-3 B. Erythromycin bite capsule bite capsule Erythromycin25-65 30-50 35-45 polyoxyethylene glycol  5-70 30-60 45-55 glycerin 5-20 7.5-15    10-12.5 flavors  1-10 2-8 3-6 C. Ciprofloxacinhydrochloride bite capsule Ciprofloxacin hydrochloride 25-65 35-55 40-50glycerin  5-20 7.5-15    10-12.5 polyethylene glycol 20-75 30-65 40-60flavors  1-10 2-8 3-6 D. zidovudine [formerly called azidothymidine(AZT) (Retrovir) lingual spray zidovudine 10-50 15-40 25-35 water 30-8040-75 45-70 ethanol  5-20 7.5-15   9.5-12.5 polyethylene glycol  5-207.5-15   9.5-12.5 flavors 0.1-5   1-4 2-3

[0040] EXAMPLE 5 Anti-emetics most preferred preferred Amounts amountamount A. Ondansetron hydrochloride lingual spray ondansetronhydrochloride  1-25  2-20 2.5-15  citric acid monohydrate,  1-10 2-82.5-5   sodium citrate dihydrate 0.5-5   1-4 1.25-2.5  water  1-90  5-8510-75 ethanol  5-30 7.5-20  9.5-15  propylene glycol  5-30 7.5-20 9.5-15  polyethylene glycol  5-30 7.5-20  9.5-15  flavors  1-10 3-8  5-7.5 B. Dimenhydrinate bite capsule Dimenhydrinate 0.5-30   2-25 3-15 glycerin  5-20 7.5-15    10-12.5 polyethylene glycol 45-95 50-9055-85 flavors  1-10 2-8 3-6 C. Dimenhydrinate polar lingual sprayDimenhydrinate  3-50  4-40  5-35 water  5-90 10-80 15-75 ethanol  1-80 3-50  5-10 polyethylene  1-80  3-50  5-15 glycol Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4 2-3

[0041] EXAMPLE 6 Histamine H-2 receptor antagonists most preferredpreferred Amounts amount amount A. Cimetidine hydrochloride bite capsuleCimetidine Hcl 10-60 15-55 25-50 glycerin  5-20 7.5-15    10-12.5polyethylene glycol 20-90 25-85 30-75 flavors  1-10 2-8 3-6 B.Famotidine lingual spray Famotidine  1-35  5-30  7-20 water 2.5-25  3-20  5-10 L-aspartic acid 0.1-20   1-15  5-10 polyethylene glycol20-97 30-95 50-85 flavors 0.1-10    1-7.5 2-5 C. Famotidine non-polarlingual spray Famotidine  1-35  5-30  7-20 Soya oil 10-50 15-40 15-20Butane 15-80 30-75 45-70 polyoxyethyl- 10-50 15-40 15-20 ated oleicglycerides flavors 0.1-5   1-4 2-3

[0042] EXAMPLE 7 Barbiturates most preferred preferred Amounts amountamount A. Phenytoin sodium lingual spray Phenytoin sodium 10-60 15-5520-40 water 2.5-25   3-20  5-10 ethanol  5-30 7.5-20  9.5-15  propyleneglycol  5-30 7.5-20  9.5-15  polyethylene glycol  5-30 7.5-20  9.5-15 flavors  1-10 3-8   5-7.5 B. Phenytoin non-polar lingual spray Phenytoin 5-45 10-40 15-35 migylol 10-50 15-40 15-20 Butane 15-80 30-75 60-70polyoxyethyl- 10-50 15-40 15-20 ated oleic glycerides flavors 0.1-10 1-8   5-7.5

[0043] EXAMPLE 8 Prostaglandins most preferred preferred Amounts amountamount A. Carboprost thromethamine lingual spray Carboprostthromethamine 0.05-5   0.1-3   0.25-2.5  water 50-95 60-80 65-75 ethanol 5-20 7.5-15   9.5-12.5 polyethylene glycol  5-20 7.5-15   9.5-12.5sodium chloride  1-20  3-15 4-8 flavors 0.1-5   1-4 2-3 pH is adjustedwith sodium hydroxide and/or hydrochloric acid B. Carboprost non-polarlingual spray Carboprost 0.05-5   0.1-3   0.25-2.5  migylol 25-50 30-4535-40 Butane  5-60 10-50 20-35 polyoxyethyl- 25-50 30-45 35-40 atedoleic glycerides flavors 0.1-10  1-8   5-7.5

[0044] EXAMPLE 9 Neutraceuticals most preferred preferred Amounts amountamount A. Carnitine as bite capsule (contents are a paste) Carnitinefumarate  6-80 30-70 45-65 soya oil 7.5-50  10-40 12.5-35   soyalecithin 0.001-1.0  0.005-0.5  .01-0.1 Soya fats 7.5-50  10-40 12.5-35  flavors  1-10 2-8 3-6 B. Valerian as lingual spray Valerian extract0.1-10  0.2-7   0.25-5   water 50-95 60-80 65-75 ethanol  5-20 7.5-15  9.5-12.5 polyethylene glycol  5-20 7.5-15   9.5-12.5 flavors  1-10 2-83-6 B. Echinacea as bite capsule Echinacea extract 30-85 40-75 45-55soya oil 7.5-50  10-40 12.5-35   soya lecithin 0.001-1.0  0.005-0.5 .01-0.1 Soya fats 7.5-50  10-40 12.5-35   flavors  1-10 2-8 3-6 B.Mixtures of ingredients Magnesium oxide 15-40 20-35 25-30 Chromiumpicolinate 0.01-1.0  0.02-0.5  .025-0.75 folic acid .025-3.0  0.05-2.0 0.25-0.5  vitamin B-12 0.01-1.0  0.02-0.5  .025-0.75 vitamin E 15-4020-35 25-30 Soya oil 10-40 12.5-35   15-20 soya lecithin 0.1-5   0.2-4  0.5-1.5 soya fat 10-40 15-35 17.5-20  

[0045] EXAMPLE 10 Sleep Inducers (also CNS active amine) most preferredpreferred Amounts amount amount A. Diphenhydramine hydrochloride lingualspray Diphenhydramine  3-50  4-40  5-35 Hcl water  5-90 10-80 50-75ethanol  1-80  3-50  5-10 polyethylene  1-80  3-50  5-15 glycol Sorbitol0.1-5   0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors0.1-5   1-4 2-3

[0046] EXAMPLE 11 Anti-Asthmatics-Bronchodilators most preferredpreferred Amounts amount amount A. Isoproterenol Hydrochloride as polarlingual spray Isoproterenol 0.1-10  0.2-7.5 0.5-6   Hydrochloride water 5-90 10-80 50-75 ethanol  1-80  3-50  5-10 polyethylene  1-80  3-50 5-15 glycol Sorbitol 0.1-5   0.2-4   0.4-1.0 aspartame 0.01-0.5 0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3 B. Terbutaline sulfate aspolar lingual spray Terbutaline 0.1-10  0.2-7.5 0.5-6   sulfate water 5-90 10-80 50-75 ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5   0.2-4  0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3C. Terbutaline as non-polar lingual spray Terbutaline 0.1-10  0.2-7.50.5-6   migylol 25-50 30-45 35-40 isobutane  5-60 10-50 20-35polyoxyethylated 25-50 30-45 35-40 oleic glycerides flavors 0.1-10  1-8  5-7.5 D. Theophylline polar bite capsule Theophylline  5-50 10-4015-30 polyethylene 20-60 25-50 30-40 glycol glycerin 25-50 35-45 30-40propylene glycol 25-50 35-45 30-40 flavors 0.1-5   1-4 2-3 E. Albuterolsulfate as polar lingual spray Albuterol sulfate 0.1-10  0.2-7.5 0.5-6  water  5-90 10-80 50-75 ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4 2-3

[0047] EXAMPLE 12 Polar solvent formulations using a propellant: Most-Preferred Preferred Amount Amount Amount A. Sulfonylurea Glyburide0.1-25%   0.5-15%   0.6-10%  Ethanol 40-99%  60-97%  70-97% Water0.01-5%    0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5%Propellant 2-10% 3-5%  3-4% B. Prostaglandin E₁ (vasodilator)Prostaglandin E₁ 0.01-10%   0.1-5%   0.2-3%   Ethanol 10-90%  20-75% 25-50% Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5%    0.1-4%  0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5% Propellant 2-10% 3-5% 3-4% C. Promethazine (antiemetic, sleep inducer, and CNS active amine)Promethazine 1-25% 3-15%  5-12% Ethanol 10-90%  20-75%  25-50% Propyleneglycol 1-90% 5-80% 10-75% Water 0.01-5%    0.1-4%   0.2-2%   Flavors0.05-10%   0.1-5%   0.1-2.5% Propellant 2-10% 3-5%  3-4% D. MeclizineMeclizine 1-25% 3-15%  5-12% Ethanol 1-15% 2-10% 3-6% Propylene glycol20-98%  5-90% 10-85% Water 0.01-5%    0.1-4%   0.2-2%   Flavors0.05-10%   0.1-5%   0.1-2.5% Propellant 2-10% 3-5%  3-4%

1. A buccal polar pump spray composition for transmucosal administrationof a pharmacologically active compound soluble in a pharmacologicallyacceptable polar solvent said composition comprising in weight % oftotal composition: polar solvent 37-98.58%, active compound 0.005-55%wherein the active compound is selected from the group consisting ofbiologically active peptides, central nervous system active amines,sulfonyl ureas, antibiotics, antifungals, antivirals, sleep inducers,antiasthmatics, antiemetics, histamine H-2 receptor antagonists,barbiturates, prostoglandins, bronchial dilators selected from the groupconsisting of terbutaline, and theophylline.
 2. The composition of claim1 additionally comprising, by weight of total composition: flavoringagent 0.1-10%.
 3. The composition of claim 1 comprising: polar solvent60.9-97.06%, active compound 0.01-40%, flavoring agent 0.75-7.5%.
 4. Thecomposition of claim 1 wherein the polar solvent is selected from thegroup consisting of low molecular weight polyethylene-glycols (PEG) of400-1000 MW, C₂-C₈ mono- and poly-alcohols, and alcohols of C₇-C₁₈hydrocarbons of a linear or branched configuration.
 5. The compositionof claim 1 wherein the solvent is aqueous polyethylene glycol.
 6. Thecomposition of claim 1 wherein the solvent comprises aqueous ethanol. 7.The composition of claim 1 wherein the active compound is selected fromthe group consisting of cyclosporin, clozapine, zidevudine,erythromycin, odansetron, cimetidine, phenytoin, carboprostthromethamine, and valerian in their nonionized form or as thepharmaceutically acceptable salts thereof.
 8. The composition of claim 2wherein the flavoring agents are selected from the group consisting ofsynthetic or natural oil of peppermint, oil of spearmint, citrus oil,fruit flavors, sweeteners and combinations thereof.
 9. The compositionof claim 2 of the formulation: polar solvent 75-85%, cyclosporin 15-25%,flavoring agent 0.1-5%.
 10. The composition of claim 2 of theformulation: polar solvent 19-90%, odansitron hydrochloride 2.5-15%,flavoring agent 1-10%.
 12. A method of administering a pharmacologicallyactive compound to a mammal in needed of same, by spraying the oralmucosa of said mammal with a composition of claim
 1. 13. The method ofclaim 12 wherein the amount of spray administered is predetermined.